Type IV Collagenases and Blood-Brain Barrier Breakdown in Brain Ischemia

Abstract

Stability of the neuronal microenvironment is indispensable for maintaining the normal function of the brain. The blood-brain barrier (BBB) is dedicated to the preservation of cerebral homeostasis. The functional features of BBB are a low diffusional permeability to water-soluble molecules, a low hydraulic conductivity,. a high reflection coefficient, and a high electrical resistance. These characteristics of BBB permit a highly selective exchange between blood and brain and an optimally controlled environment in the physiological state. As a functional entity, BBB includes several cell types and the extracellular matrix (ECM). Microvascular endothelial cells (EC) sealed by tight junctions and featuring only a very few endocytotic vesicles are primarily responsible for the permeability properties of BBB (1). Astrocytes, in discontinuous contact with endothelial cells through their end-feet, actively participate in BBB phenotype (2), although some controversy exists regarding the importance of astrocytes in the in vivo maintenance of BBB function (3,4). Pericytes also have been shown to change endothelial behavior (5–7). These perivascular cells seem to control angiogenesis by inhibiting EC proliferation (8) and to regulate microvessel permeability by contributing to basal lamina synthesis (9,10). Finally, the endothelial basal lamina represents the noncellular component of BBB. Produced by EC and pericytes, the basal lamina is a specialized ECM composed of type IV collagen, fibronectin, laminin, and various proteoglycans (11). The ECM components are linked to endothelial cells via integrins and regulate specific biological processes such as cellular morphology, differentiation, survival, adhesion, and gene expression (12–15).